Mastitis is the most common disease of dairy cattle. In commercial herds, the cost due to reduced milk quality can be extremely significant. This cost can be due to reduced production and the need to withhold contaminated milk from the processing stream. Mastitis is an inflammatory response of the udder tissue due to some form of injury, the most common being bacterial infection. The inflammatory response consists of an increase in blood proteins and white blood cells in the mammary tissue and the milk. The Somatic Cell Count, SCC, increases from about 200,000 SC/mL of milk (uninfected) to over 300,000 SC/mL of milk (inflamed/infected). The purpose of this response is to destroy the irritant, repair the damaged-tissue and return the udder to normal function. Inflammation is characterized by: (a) swelling of the udder where persisting inflammation leads to tissue damage and replacement of secretory tissues within the udder with nonproductive connective tissues, (b) clotting of the milk, wherein these clots are congealed leukocytes, secretory cells and protein and (c) a lower milk yield. Moreover, milk contamination exposes human consumers to diseases including tuberculosis, sore-throat, Q-fever, brucellosis, leptospirosis etc.
Mastitis begins after bacteria pass through the teat canal and enter the part of the teat known as the cistern. Significant mastitis-causing pathogens include, but are not limited to, Staphylococcus spp. (including S. aureus), Streptococcus spp. (including S. agalactiae and S. dysgalactiae, and S. uberis) and E. coli. There are two major periods during which this can occur: during the lactation period or during the non-lactation (dry) period. During the lactation period invasion of the teat usually occurs during milking. After milking, the teat canal remains dilated for 1-2 hours while the canal of a damaged teat may remain partially open permanently. This makes it easier for organisms from the environment or those found on injured skin to enter the teat canal. Adherence of bacteria to tissues lining cisterns and ducts may prevent flushing-out during milking and help establish infections. Bacteria eventually enter the glandular tissues where they affect alveolar cells. Toxins produced by bacteria cause death of or damage to milk-secreting epithelial cells, and these cells produce substances to the blood stream that increase blood vessel permeability. This allows leukocytes to move from the blood into the alveolus where they function by engulfing bacteria.
At the conclusion of the lactation period and once milking has stopped for the season the teat canal is closed by the formation of a natural keratin teat plug. This typically happens over a period of 2-3 weeks. However prior to the formation of this teat plug the teat canal is open and highly susceptible to bacterial infection. It can also be the case that if the teat plug is poorly developed there is an opportunity for on-going infection. Indeed it takes between one and nine weeks for most cows to form this plug and up to 5% of cows never form one. Typically 50% of teats may still be “open” at 10 days after drying off (see, e.g., Williamson J H, Woolford M W, Day A M. The prophylactic effect of a dry cow antibiotic against Streptococcus uberis. New Zealand Veterinary Journal (1995) 43, 228-234).
To prevent new cases of mastitis during the dry period many farmers treat cows with a prophylactic treatment of an intramammary antibiotic. This is administered in the form of a paste or gel infused with antibiotic. A syringe is used to insert the material directly into the teat canal via the opening at the base of the teat. Prevention of mastitis is reliant on sufficient antibiotic being retained in the teat canal to kill off any bacteria that may enter the teat canal over the dry period. However more recently there has been increased concern regarding the use of traditional antibiotics (e.g. beta-lactams, macrolides, and the like) in dairy cows. This is due to two reasons: (a) the potential for antibiotic residues in milk, which can cause milk processors problems in producing culture-based dairy products and (b) the potential for the development of bacterial resistance to antibiotics crossing from animal to human strains. It would therefore be highly desirable to develop new antimicrobial agents, and methods and compositions for delivering same, which do not suffer from these drawbacks, to address the costly problem of dairy cow mastitis. Such improved antimicrobial agents could equally well guard animals against a host of pathogens, including those that enter via susceptible membranes (e.g. mouth, nose, lungs, etc.), wounds, and post-operative incisions.
For additional background regarding the state-of-the art, please see US 2010/0143510 A1, to Merial Limited; U.S. Pat. No. 6,740,322 B2, to the University of Saskatchewan; and WO 2014/001353 A1, to Bayer Animal Health.